CA2914606C - Benzothiophene compound - Google Patents
Benzothiophene compound Download PDFInfo
- Publication number
- CA2914606C CA2914606C CA2914606A CA2914606A CA2914606C CA 2914606 C CA2914606 C CA 2914606C CA 2914606 A CA2914606 A CA 2914606A CA 2914606 A CA2914606 A CA 2914606A CA 2914606 C CA2914606 C CA 2914606C
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- CA
- Canada
- Prior art keywords
- compound
- salt
- pain
- methyl
- chloro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- -1 Benzothiophene compound Chemical class 0.000 title claims abstract description 30
- FCEHBMOGCRZNNI-UHFFFAOYSA-N thianaphthalene Natural products C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 title abstract description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 128
- 208000002193 Pain Diseases 0.000 claims abstract description 30
- 230000036407 pain Effects 0.000 claims abstract description 30
- 208000001640 Fibromyalgia Diseases 0.000 claims abstract description 28
- 206010065390 Inflammatory pain Diseases 0.000 claims abstract description 28
- 208000004296 neuralgia Diseases 0.000 claims abstract description 27
- 208000021722 neuropathic pain Diseases 0.000 claims abstract description 27
- 239000003814 drug Substances 0.000 claims abstract description 19
- 208000009935 visceral pain Diseases 0.000 claims abstract description 18
- 150000003839 salts Chemical class 0.000 claims description 68
- 125000000217 alkyl group Chemical group 0.000 claims description 33
- 201000008482 osteoarthritis Diseases 0.000 claims description 30
- 229910052736 halogen Inorganic materials 0.000 claims description 19
- 150000002367 halogens Chemical class 0.000 claims description 16
- 239000008194 pharmaceutical composition Substances 0.000 claims description 13
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
- 201000010099 disease Diseases 0.000 claims description 8
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 2
- 108010033149 Intermediate-Conductance Calcium-Activated Potassium Channels Proteins 0.000 claims description 2
- 102000007008 Intermediate-Conductance Calcium-Activated Potassium Channels Human genes 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 239000004036 potassium channel stimulating agent Substances 0.000 claims description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 6
- IOWRHVVSRLGDKK-LJQANCHMSA-N 5-(6-chloro-2-methyl-1-benzothiophen-3-yl)-2-[(2r)-2-[(cyclobutylamino)methyl]morpholin-4-yl]benzoic acid Chemical compound C([C@H]1OCCN(C1)C1=CC=C(C=C1C(O)=O)C=1C2=CC=C(Cl)C=C2SC=1C)NC1CCC1 IOWRHVVSRLGDKK-LJQANCHMSA-N 0.000 claims 2
- CNMAHJRSKHFBQG-MRXNPFEDSA-N 2-[(3r)-3-[(tert-butylamino)methyl]piperidin-1-yl]-5-[6-(trifluoromethyl)-1-benzothiophen-3-yl]benzoic acid Chemical compound C1[C@@H](CNC(C)(C)C)CCCN1C1=CC=C(C=2C3=CC=C(C=C3SC=2)C(F)(F)F)C=C1C(O)=O CNMAHJRSKHFBQG-MRXNPFEDSA-N 0.000 claims 1
- BIACSKOCQXVCTM-QGZVFWFLSA-N 5-(6-chloro-2-fluoro-1-benzothiophen-3-yl)-2-[(2r)-2-[(cyclobutylamino)methyl]morpholin-4-yl]benzoic acid Chemical compound C([C@H]1OCCN(C1)C1=CC=C(C=C1C(=O)O)C=1C2=CC=C(Cl)C=C2SC=1F)NC1CCC1 BIACSKOCQXVCTM-QGZVFWFLSA-N 0.000 claims 1
- AKAPRLWYPCCXRD-QGZVFWFLSA-N 5-(6-chloro-5-fluoro-2-methyl-1-benzothiophen-3-yl)-2-[(2R)-2-[(cyclobutylamino)methyl]morpholin-4-yl]benzoic acid Chemical compound Cc1sc2cc(Cl)c(F)cc2c1-c1ccc(N2CCO[C@H](CNC3CCC3)C2)c(c1)C(O)=O AKAPRLWYPCCXRD-QGZVFWFLSA-N 0.000 claims 1
- CGAJHTSRDXRFJT-MRXNPFEDSA-N 5-[5-chloro-6-(trifluoromethyl)-1-benzothiophen-3-yl]-2-[(2r)-2-[(cyclobutylamino)methyl]morpholin-4-yl]benzoic acid Chemical compound C([C@H]1OCCN(C1)C1=CC=C(C=C1C(=O)O)C=1C2=CC(Cl)=C(C=C2SC=1)C(F)(F)F)NC1CCC1 CGAJHTSRDXRFJT-MRXNPFEDSA-N 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 16
- 239000012190 activator Substances 0.000 abstract description 11
- 230000003349 osteoarthritic effect Effects 0.000 abstract 3
- 230000003213 activating effect Effects 0.000 abstract 1
- 238000012790 confirmation Methods 0.000 abstract 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 78
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 77
- 235000002639 sodium chloride Nutrition 0.000 description 51
- 238000002360 preparation method Methods 0.000 description 47
- 239000000203 mixture Substances 0.000 description 42
- 239000011541 reaction mixture Substances 0.000 description 42
- 238000012360 testing method Methods 0.000 description 41
- 238000005481 NMR spectroscopy Methods 0.000 description 36
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 35
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 34
- 238000003756 stirring Methods 0.000 description 34
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 28
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 28
- 239000000243 solution Substances 0.000 description 27
- 108091006146 Channels Proteins 0.000 description 26
- 239000012044 organic layer Substances 0.000 description 26
- 239000002904 solvent Substances 0.000 description 26
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 23
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 23
- 239000012267 brine Substances 0.000 description 22
- 239000000741 silica gel Substances 0.000 description 22
- 229910002027 silica gel Inorganic materials 0.000 description 22
- 238000006243 chemical reaction Methods 0.000 description 21
- 239000003795 chemical substances by application Substances 0.000 description 21
- 239000012738 dissolution medium Substances 0.000 description 21
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 20
- 230000000694 effects Effects 0.000 description 20
- 239000007832 Na2SO4 Substances 0.000 description 19
- 229910052938 sodium sulfate Inorganic materials 0.000 description 19
- 235000011152 sodium sulphate Nutrition 0.000 description 19
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 18
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 18
- 238000000605 extraction Methods 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 17
- 125000006311 cyclobutyl amino group Chemical group [H]N(*)C1([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 14
- 229920006395 saturated elastomer Polymers 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 13
- 241000700159 Rattus Species 0.000 description 13
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 13
- 239000007858 starting material Substances 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 238000001816 cooling Methods 0.000 description 12
- 238000001914 filtration Methods 0.000 description 12
- 239000000126 substance Substances 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 10
- 238000000034 method Methods 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- 125000002947 alkylene group Chemical group 0.000 description 9
- 239000012300 argon atmosphere Substances 0.000 description 9
- 235000017557 sodium bicarbonate Nutrition 0.000 description 9
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 9
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 8
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 7
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 7
- 210000003141 lower extremity Anatomy 0.000 description 7
- 125000006239 protecting group Chemical group 0.000 description 7
- 235000017550 sodium carbonate Nutrition 0.000 description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 description 7
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 239000004480 active ingredient Substances 0.000 description 6
- 238000003556 assay Methods 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 238000009826 distribution Methods 0.000 description 6
- 230000006872 improvement Effects 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 239000012046 mixed solvent Substances 0.000 description 6
- 239000002244 precipitate Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 6
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 5
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 5
- 208000004998 Abdominal Pain Diseases 0.000 description 5
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 5
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 5
- 101100534514 Mus musculus Stmn1 gene Proteins 0.000 description 5
- 238000000692 Student's t-test Methods 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 239000011575 calcium Substances 0.000 description 5
- 229910052791 calcium Inorganic materials 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 5
- 235000019341 magnesium sulphate Nutrition 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- BJOIZNZVOZKDIG-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC(OC)=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 BJOIZNZVOZKDIG-MDEJGZGSSA-N 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 5
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 4
- DNXIKVLOVZVMQF-UHFFFAOYSA-N (3beta,16beta,17alpha,18beta,20alpha)-17-hydroxy-11-methoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]-yohimban-16-carboxylic acid, methyl ester Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(C(=O)OC)C(O)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 DNXIKVLOVZVMQF-UHFFFAOYSA-N 0.000 description 4
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 4
- LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 description 4
- QEVHRUUCFGRFIF-SFWBKIHZSA-N Reserpine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cc(OC)cc3 QEVHRUUCFGRFIF-SFWBKIHZSA-N 0.000 description 4
- 235000011054 acetic acid Nutrition 0.000 description 4
- 230000009471 action Effects 0.000 description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 4
- 125000000524 functional group Chemical group 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- JDNTWHVOXJZDSN-UHFFFAOYSA-N iodoacetic acid Chemical compound OC(=O)CI JDNTWHVOXJZDSN-UHFFFAOYSA-N 0.000 description 4
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 4
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 4
- UGUNLTUTYUTNOT-JTQLQIEISA-N methyl 5-bromo-2-[(2S)-2-(hydroxymethyl)morpholin-4-yl]benzoate Chemical compound COC(=O)c1cc(Br)ccc1N1CCO[C@H](CO)C1 UGUNLTUTYUTNOT-JTQLQIEISA-N 0.000 description 4
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 230000002265 prevention Effects 0.000 description 4
- 239000000651 prodrug Substances 0.000 description 4
- 229940002612 prodrug Drugs 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 229960003147 reserpine Drugs 0.000 description 4
- MDMGHDFNKNZPAU-UHFFFAOYSA-N roserpine Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(OC(C)=O)C(OC)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 MDMGHDFNKNZPAU-UHFFFAOYSA-N 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- NHDIQVFFNDKAQU-UHFFFAOYSA-N tripropan-2-yl borate Chemical compound CC(C)OB(OC(C)C)OC(C)C NHDIQVFFNDKAQU-UHFFFAOYSA-N 0.000 description 4
- NVSVCEJKKYMAKI-UHFFFAOYSA-N (6-chloro-2-methyl-1-benzothiophen-3-yl)boronic acid Chemical compound Cc1sc2cc(Cl)ccc2c1B(O)O NVSVCEJKKYMAKI-UHFFFAOYSA-N 0.000 description 3
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 3
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 3
- OZAIFHULBGXAKX-VAWYXSNFSA-N AIBN Substances N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 208000009386 Experimental Arthritis Diseases 0.000 description 3
- 239000012981 Hank's balanced salt solution Substances 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 102000004257 Potassium Channel Human genes 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 230000002421 anti-septic effect Effects 0.000 description 3
- JXHYCCGOZUGBFD-UHFFFAOYSA-N benzoic acid;hydrochloride Chemical compound Cl.OC(=O)C1=CC=CC=C1 JXHYCCGOZUGBFD-UHFFFAOYSA-N 0.000 description 3
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 150000002170 ethers Chemical class 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 239000002198 insoluble material Substances 0.000 description 3
- 208000002551 irritable bowel syndrome Diseases 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 3
- 108020001213 potassium channel Proteins 0.000 description 3
- 238000000634 powder X-ray diffraction Methods 0.000 description 3
- 239000008247 solid mixture Substances 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 238000001356 surgical procedure Methods 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 3
- BZHSQEBARZGORM-UHFFFAOYSA-N (6-chloro-5-fluoro-1-benzothiophen-2-yl)methanol Chemical compound OCc1cc2cc(F)c(Cl)cc2s1 BZHSQEBARZGORM-UHFFFAOYSA-N 0.000 description 2
- VMZJDAVSEGGMCF-UHFFFAOYSA-N 1-chloro-4-fluoro-2-iodo-5-methylbenzene Chemical compound Cc1cc(Cl)c(I)cc1F VMZJDAVSEGGMCF-UHFFFAOYSA-N 0.000 description 2
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- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4535—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Physical Education & Sports Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Immunology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2013119416 | 2013-06-06 | ||
| JP2013-119416 | 2013-06-06 | ||
| PCT/JP2014/065141 WO2014196644A1 (ja) | 2013-06-06 | 2014-06-06 | ベンゾチオフェン化合物 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2914606A1 CA2914606A1 (en) | 2014-12-11 |
| CA2914606C true CA2914606C (en) | 2021-03-23 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2914606A Active CA2914606C (en) | 2013-06-06 | 2014-06-06 | Benzothiophene compound |
Country Status (31)
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| US (2) | US8981119B2 (hu) |
| EP (1) | EP3006443B1 (hu) |
| JP (1) | JP6314978B2 (hu) |
| KR (1) | KR102253721B1 (hu) |
| CN (1) | CN105263926B (hu) |
| AR (1) | AR096544A1 (hu) |
| AU (1) | AU2014275768B2 (hu) |
| BR (1) | BR112015030533B1 (hu) |
| CA (1) | CA2914606C (hu) |
| CY (1) | CY1120341T1 (hu) |
| DK (1) | DK3006443T3 (hu) |
| ES (1) | ES2671818T3 (hu) |
| HK (1) | HK1215570A1 (hu) |
| HR (1) | HRP20180722T1 (hu) |
| HU (1) | HUE038920T2 (hu) |
| IL (1) | IL242800B (hu) |
| LT (1) | LT3006443T (hu) |
| MX (1) | MX2015016743A (hu) |
| NO (1) | NO3006443T3 (hu) |
| PH (1) | PH12015502637A1 (hu) |
| PL (1) | PL3006443T3 (hu) |
| PT (1) | PT3006443T (hu) |
| RS (1) | RS57250B1 (hu) |
| RU (1) | RU2667507C2 (hu) |
| SG (1) | SG11201509989VA (hu) |
| SI (1) | SI3006443T1 (hu) |
| TR (1) | TR201808724T4 (hu) |
| TW (1) | TWI624466B (hu) |
| UA (1) | UA117484C2 (hu) |
| WO (1) | WO2014196644A1 (hu) |
| ZA (1) | ZA201508866B (hu) |
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| EP4003357A1 (en) | 2019-07-23 | 2022-06-01 | Astellas Pharma Global Development, Inc. | Methods of treating sleep disorders associated with pain |
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| US5614639A (en) * | 1995-03-31 | 1997-03-25 | Eli Lilly And Company | Process for preparing 2-substituted benzo[b]thiophene compounds and intermediates thereof |
| US20040116405A1 (en) | 2001-02-06 | 2004-06-17 | Brian Cox | Use of bicyclic esters or amides for the treatment of diseases responsive to enhanced potassium channel activity |
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| CN101333192A (zh) * | 2003-04-03 | 2008-12-31 | 默克公司 | 作为钠通道阻滞剂的联芳基取代吡唑 |
| JP2007523873A (ja) | 2003-07-15 | 2007-08-23 | スミスクライン・ビーチャム・コーポレイション | 新規化合物 |
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